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14 CH 8003 BA_INTERIEUR.qxd:DCNS#55 2/12/13 17:44
Clinical research
Memory loss in Alzheimer’s disease
Holger Jahn, MD
Loss of memory is among the first symptoms reported by
patients suffering from Alzheimer’s disease (AD) and by
their caretakers. Working memory and long-term declar-
ative memory are affected early during the course of the
disease. The individual pattern of impaired memory
functions correlates with parameters of structural or
functional brain integrity. AD pathology interferes with
the formation of memories from the molecular level to
the framework of neural networks. The investigation of
AD memory loss helps to identify the involved neural
structures, such as the default mode network, the influ-
ence of epigenetic and genetic factors, such as ApoE4
status, and evolutionary aspects of human cognition.
Clinically, the analysis of memory assists the definition of
AD subtypes, disease grading, and prognostic predic-
tions. Despite new AD criteria that allow the earlier diag-
nosis of the disease by inclusion of biomarkers derived
from cerebrospinal fluid or hippocampal volume analy-
sis, neuropsychological testing remains at the core of AD
diagnosis.
© 2013, AICH – Servier Research Group Dialogues Clin Neurosci. 2013;15:445-454.
Keywords: memory; Alzheimer’s disease; neuropsychological test; brain atrophy;
default mode network
Copyright © 2013 AICH – Servier Research Group. All rights reserved
Page 445
Introduction
A sked to name a disease that affects “memory,”
most physicians would probably choose Alzheimer’s dis-
ease (AD). AD is the most common cause of dementia.
Currently, 30 million people worldwide suffer from
Alzheimer’s dementia and the World Health organiza-
tion projects that this number will triple over the next 20
years.1 The cumulative incidence of Alzheimer dementia
has been estimated to rise from about 5% by age 70 to
50% by age 90, making it a very common disease.2
Increasing longevity and demographic shifts in many
societies will stress the health systems unless a cure for
AD is found—or at least any therapy that postpones the
onset of the dementia by 5 to 10 years for the time being.
AD is a polygenetic neurodegenerative brain disorder
characterized by neocortical atrophy developing over
decades, showing the increasing loss of synapses and neu-
rons first described by Alois Alzheimer in 1907.3
Variations in the genes encoding the amyloid precursor
proteins, presenilin-1 and presenilin-2, can directly cause
Alzheimer’s disease. The patients often display an early
onset of dementia in their forties, and these determinis-
tic genes affect whole families and patients with trisomy
21. They, however, account for only 1% of all cases of
AD. The remaining 99% of sporadic AD occurs pre-
Author affiliations: University Hospital Hamburg-Eppendorf, Dept of
Psychiatry and Psychotherapy, Hamburg, Germany
Address for correspondence: Holger Jahn, MD, University Hospital Hamburg-
Eppendorf, Dept of Psychiatry and Psychotherapy, Martinistr. 52, 20246
Hamburg, Germany
(e-mail: jahn@uke.de)
445 www.dialogues-cns.org
14 CH 8003 BA_INTERIEUR.qxd:DCNS#55 2/12/13 17:44 Page 446
Clinical research
Selected abbreviations and acronyms
DMN default mode network
DTI diffusion tensor imaging
FA fractional anisotropy
FX fragile X
HARDI high angular resolution diffusion imaging
ICA independent components analysis
TBM tensor-based morphometry
VBM voxel-based morphometry
dominantly in patients older than 65 years.4 These
patients also inherit 60% to 80% of their risk for late-
onset AD, although it is not connected to the aforemen-
tioned genes, with the remainder being environmental.4,5
In late-onset AD many different genes—some still
unidentified—are involved, each only attributing a minor
fraction of the individual’s overall risk, making it a pos-
sible example of antagonistic pleiotropy.6 Recently, sev-
eral genome-wide association studies have identified new
candidates (for reviews and databases see http://www.alz-
gene.org). The best characterized genetic risk factor in
late-onset AD is the apolipoprotein E4 (ApoE4) geno-
type with ApoE4 carriers having a 4- to 10-fold increased
odds ratio of developing AD.7 The ApoE4 allele is an
ancestral variant. The human ApoE2 and ApoE3 alleles
are fairly recent mutations—less than 200 000 years old.8
ApoE3 is the most frequent allele, with frequencies of
about 60% in human populations. In contrast, ApoE4 has
a frequency of about 10%. This implies that ApoE3 and
ApoE2 must possess an advantage in order to have
gained prevalence in human populations so quickly; clin-
ical and preclinical data point to higher synaptic plastic-
ity and repair capacities in carriers of ApoE2 and ApoE3,
which may explain the selection bias.9 The consumption
and adaption of humans to a diet rich in meat and animal
fats can also be a reason for the selection of ApoE3.10
Atrophy in AD
The neuropathological hallmarks of the atrophy process
in AD are the presence of senile plaques (amyloid
deposits) and neurofibrillary tangles in autopsied brains.11
Neurofibrillary tangles are composed of hyperphospho-
rylated tau protein located within neurons, whereas senile
plaques are made up largely of amyloid-β species aggre-
gating in the extracellular space. These neuropathological
changes start in the entorhinal cortex and hippocampal
formations, later spreading into other temporal, parietal,
446
and finally frontal association cortices.12-14 The first lesions
characteristic of AD appear in poorly myelinated limbic
neurons in system areas related to memory and learning,
such as the hippocampus and the association cortex.
Highly myelinated neurons are only affected in the final
phases of the disease.15 Low myelinization increases the
overall energy expenditure of neurons. In addition, sub-
cortical neuron loss occurs in the nucleus basalis of
Meynert and the locus ceruleus, impairing the cholinergic
and noradrenergic transmitter systems in the neocor-
tex.16,17 The parietal lobe, along with certain areas of the
prefrontal lobe, is one of the last areas of the human brain
to myelinate, and many of its neurons remain poorly
myelinated for the entire lifespan, which may explain their
vulnerability to factors capable of triggering AD.18-20 The
atrophy runs slowly, but while in healthy aging only 0.2%
to 0.41% of the brain volume vanishes per year, the rates
in AD may be ten times that, and in especially vulnerable
regions like the hippocampal formation atrophy rates
might be even more devastatingly high and surpass 10%
per year (see also Figure 1).21-23 In terms of neuropsycho-
C Hippocampus left
D Lateral ventricle left
Lateral ventrical volume (mL)
60
Hippocampal volume (mL)
2.5
50
2
40
1.5
30
1
68 70 72 68 70 72
Age (y) Age (y)
Figure 1. Atrophy in a case of AD over 4 years. (A) Reduction of gray mat-
ter (lateral view; corrected for age; P<0.05), (B) coronal view of
the left hippocampus at baseline and after 4 years (hippocam-
pal gray matter volume at T0 5.3±0.4 mL, at T4 3.5±0.2 mL),
(C) average hippocampal volume reduction of 0.2 mL per year
(–12%/year), (D) average increase of lateral ventricle volume of
2.7 mL/per year (+ 6.7%/year).
(Courtesy of L. Spies, Jung-diagnostics GmbH, Hamburg, Germany)
14 CH 8003 BA_INTERIEUR.qxd:DCNS#55 2/12/13 17:44 Page 447
Memory loss in AD - Jahn
logical tests, regional atrophy, and glucose metabolism
correlate well with test results.24,25 Left hippocampal gray
matter volume, for example, significantly correlates with
performance in memory tasks, and left temporal gray
matter volume is related to performance in language
tasks. The rate of change in the left hippocampus corre-
lates with decline of performance in the Boston Naming
Test Mini-Mental Status Examination, and the trailmak-
ing test B.24 Such analyses help with the definition of spe-
cial AD subtypes like posterior cortical atrophy, or the
logopenic variant of AD.24-31 On the molecular level we
find a downregulation of synaptic genes across multiple
brain regions and widespread proteomic signs of synaptic
stress or decay in the cerebrospinal fluid (CSF) or blood.32-
34
Changes in the molecular fine structure of AD brains
also arise independently of atrophy as resonance spec-
troscopic investigations in AD imply.35
This review aims to highlight some aspects concerning
the development of memory deficits in AD that recently
have or should have gained attention.
Impact of new diagnostic criteria
Recently workgroups of the Alzheimer’s Association and
the National Institute on Aging have issued new criteria
and guidelines to diagnose Alzheimer’s disease supplant-
ing the previous guidelines first published in 1984.36-40 This
marks a complete overhaul, and attemps to implement
advances in our understanding of the disease in the way
we diagnose the disease. The most notable differences are
the use of biomarkers such as hippocampal atrophy, and
the formalization of earlier disease stages before demen-
tia is apparent, such as mild cognitive impairment due to
AD and the newly defined preclinical AD stage.38,39 While
the recommendations of the preclinical AD workgroup
are intended purely for research purposes and the aim of
diagnosing the disease earlier appears sensible since it is
likely that any intervention has to be started early to be
successful, it is also clear that we would almost all be
defined as having the disease using this definition, given
the increasing prevalence of AD in the very old. From a
scientific point of view, it might be more interesting to
know why a few of us might not develop AD, even when
we are not dying from other diseases. As clinicians AD
patients may first approach us with mere subjective con-
cerns about cognitive decline. This can develop into mild
cognitive impairment with pathological neuropsycho-
logical test results and progress into dementia, at which
447
Dialogues in Clinical Neuroscience - Vol 15 . No. 4 . 2013
time daily activities can no longer be performed properly.
When brain atrophy progresses other psychiatric and
neurological symptoms arise, and typically AD patients
lose weight and frequently develop difficulties in swal-
lowing. This may lead to aspiration and subsequently
pneumonia, which is often the final cause of death in
demented patients.
The neuropsychology of AD:
tests and what they indicate
Consensus exists that AD starts clinically with memory
complaints, which may affect episodic memory, speech
production, with naming or semantic problems, or visual
orientation. Memory can be defined as a process of
encoding, storing, and retrieving information about outer
and inner stimuli, or presentation of information to the
nervous system of an organism that can be used to react
and position the organism towards new stimuli. Different
categories of memory have been defined which also have
different neuroanatomical and neurophysiological cor-
relates: short-term memory vs long-term memory or
implicit versus declarative memory. Short-term memory
is limited to just a few “chunks” in capacity, and lasts only
seconds to minutes.41 It depends on regions of the frontal
lobe and the parietal lobe. In contrast, long-term mem-
ory seems almost limitless regarding its storage capaci-
ties, for a potentially unlimited duration. It depends on
de novo protein synthesis and changes in the molecular
components of the neuronal networks involved in the
specific cortical areas that can be attributed to different
memory types. Declarative memory, for example, can be
further subdivided into semantic memory, where context-
independent information is stored, and episodic memory,
which stores information specific to a particular context,
mainly time and place. Semantic memory is at first
impaired in the language of AD patients, affecting verbal
fluency and naming. Semantic loss in AD may occur sev-
eral years prior to diagnosis.42 The hippocampus is essen-
tial to the consolidation of information from short-term
to long-term memory. Destruction of the hippocampal
formation makes the storage of new memories impossi-
ble. In the clinical context we use neuropsychological test
batteries like the CERAD (Consortium to Establish a
Registry for Alzheimer’s Disease) examination, the Mini-
Mental State examination, and various other test con-
structs and scales, like the clinical dementia rating scale,
that investigate different aspects of memory over a broad
14 CH 8003 BA_INTERIEUR.qxd:DCNS#55 2/12/13 17:44 Page 448
Clinical research
range of various cognitive domains.43-45 Patients get pro-
filed in relation to tests they show abnormalities on, com-
pared with a healthy reference group adjusted for age
and education. AD patients typically display a cognitive
profile with impairments in multiple cognitive domains.
This cognitive profile develops over time, and AD
patients often start to show a progressive decay of work-
ing memory. The patients display increased sensitivity to
distraction in memory tasks, the capacity of working
memory measured, eg, digit span is, however, at first still
intact. Interestingly, the medications used currently to
treat AD like acetylcholinesterase inhibitors or meman-
tine work partly by increasing attention and concentra-
tion and work mainly in mild-to-moderate AD.46,47
The deficits in attention and working memory associated
with damage to frontal subcortical circuits also influence
executive functions in AD, impairing planning, problem
solving, and goal-directed behavior such as the ability to
deploy response alternatives or modify behavior. AD
patients show impaired results in tests that require plan-
ning, problem solving, or cognitive flexibility, eg, the
Wisconsin Card Sorting Test, the Stroop test, or the
Tower of London Test. The manifestation of impairment
in such tests of executive functioning corresponds to the
onset of difficulties in the performance of daily activities
in these patients and marks the progression to the state
of full dementia. The Boston Naming test assesses the
ability to name pictures of objects through spontaneous
responses, and the need for various types of cueing.
Cued recall deficits are most closely associated with CSF
biomarkers indicative of AD in subjects with mild cog-
nitive impairment. This novel finding complements
results from prospective clinical studies and provides
further empirical support for cued recall as a specific
indicator of prodromal AD, in line with recently pro-
posed research criteria.48 Another surprisingly simple
test is the Clock Drawing test. AD patients show early
difficulties in visuospatial processing and conceptual
errors like misrepresentation of numbers in the com-
mand, but not in the copy, condition, pointing to deficits
in semantic memory. The Trail Making Test A+B is a
neuropsychological test of visual attention measuring
mental processing speed, and the ability to switch
between different tasks. It consists of two parts in which
the subject is asked to connect a set of 25 dots as fast as
possible while maintaining accuracy. Visual search speed,
scanning and processing abilities, mental flexibility, and
executive functioning can be assessed with this test.
448
Regarding animal models, there are plenty of paradig-
mata available to test memory functions, but there is an
overall lack of validated animal data that can be aligned
with similar tests in human settings. Snigdha et al started
with the comprehensive toolbox for Neurologic
Behavioral Function from the National Institutes of
Health (NIH) which contains evaluated tests for cogni-
tive, motor, sensory, and emotional function for use in
epidemiologic and clinical studies spanning 3 to 85 years
of age and analyzed strengths and limitations of avail-
able animal behavioral tests to find matches. They
defined a preclinical battery that aims to parallel the
NIH Toolbox, and may help to close the gap between
data from different species.49
Subjective cognitive impairment
Subjective cognitive impairment without detectable
objective memory deficit may no longer merely
regarded as “normal aging” since it has been shown that
it is a major risk factor for the development of demen-
tia.50 A clear definition of what subjective memory
impairment or subjective cognitive impairment actually
mean is currently lacking. An international task force is,
however, working on standard operating procedures that
would enable comparable study designs. A consensus
regarding naming the concept “subjective cognitive
impairment” in view of previously used terminology
such as “subjective memory impairment” seems to be
arising. Subjective cognitive impairment is defined as the
individual coming up with the mere feeling that some-
thing is not in order, without any objective parameters
supporting that notion in the first place. Such a stage
labeled subjective cognitive impairment may precede
mild cognitive impairment in the continuum of
Alzheimer disease manifestation. Using such a defini-
tion and without objective neuropsychological test alter-
ations, the atrophy pattern of patients with subjective
cognitive impairment seem to be related to the atrophy
pattern seen in AD.51 Individuals with subjective mem-
ory impairment showed greater similarity to an AD gray
matter pattern, and episodic memory decline was asso-
ciated with an AD gray matter pattern in probands with
subjective memory impairment.52 Patients with subjec-
tive memory impairment also already showed hypome-
tabolism in the right precuneus and hypermetabolism in
the right medial temporal lobe using (fludeoxyglucose
positron emission tomography, FDG-PET). Their gray
14 CH 8003 BA_INTERIEUR.qxd:DCNS#55 2/12/13 17:44 Page 449
Memory loss in AD - Jahn
matter volume was reduced in the right hippocampus. At
follow-up, these patients showed poorer performance on
measures of episodic memory. The observed memory
decline was associated with reduced glucose metabolism
in the right precuneus at baseline. The authors conclude
that their concept of subjective memory impairment
may define the earliest clinical manifestation of AD.53 In
another study patients with subjective memory under-
went an associative episodic memory task matching
faces to professions, including encoding, recall, and
recognition, and a working memory task during func-
tional magnetic resonance imaging (fMRI). They
showed a reduction in right hippocampal activation dur-
ing episodic memory recall, still in the absence of per-
formance deficits. This was accompanied by increased
activation of the right dorsolateral prefrontal cortex. No
such differences in performance and brain activation
were detected for working memory. This may indicate
subtle early neuronal dysfunction on the hippocampal
level and compensatory mechanisms that preserve mem-
ory performance.54
Regarding ApoE4, cognitively unimpaired young elderly
with and without subjective memory impairment were
tested on episodic memory and on tasks of speed and
executive function. Medial temporal lobe volumetric
measures were calculated from MRI images. In the sub-
jective memory impairment group, ApoE4 carriers per-
formed worse on the episodic memory and showed
smaller left hippocampal volumes. In the individuals
without memory complaints, the ApoE4 carriers per-
formed better on episodic memory and had larger right
hippocampal volumes (P=0.039). The interaction of
group and ApoE genotype was significant for episodic
memory and right and left hippocampal volumes. The
negative effect of ApoE4 on episodic memory and hip-
pocampal volume in the group suffering from subjective
memory decline also supports the notion that this may
be a prodromal condition of AD.55 In conclusion, the
mere subjective feeling of being cognitively altered com-
pared with the individual’s reference past can already be
accompanied by subtle brain changes that if ongoing
may herald increasing memory decline in the future.
Memory of smell
Impaired sense of smell or hyposmia is one of the ear-
liest clinical features in neurodegenerative disorders like
both AD or Parkinson’s disease.56 This has been known
449
Dialogues in Clinical Neuroscience - Vol 15 . No. 4 . 2013
for decades and relates well to the finding that, for
example, plaque formation in AD starts in the entorhi-
nal cortex, the region also responsible for processing of
information on smell. A recent meta-analysis of 81 stud-
ies indicated that AD and PD patients are more
impaired on odor identification and recognition tasks
than on odor detection threshold tasks. AD patients
were found to be more impaired on higher-order olfac-
tory tasks involving specific cognitive processes.57 Odor
identification and recognition tests can be easily imple-
mented in cognitive test batteries to detect already sub-
clinical cases of AD. The impairment of smell recogni-
tion is of clinical importance, as patients often report
malodorous sensations and changes in, eg, the taste of
foods leading to behavioral alterations. Consequences
may range from increasing malnutriton to the develop-
ment of delusions of poisoning that may trigger aggres-
sive behavior. The deterioration of the neural network
in the entorhinal cortex leads to an impairment in the
ability to store and retrieve different representations of
smell, with the decaying network yielding increasingly
“default values” that have the tendency to be of rather
unpleasant character. This feature of the neural network
of smell memory reflects the evolutionary pressure
towards the secure recognition of “bad” smells pointing
to poisonous or rotten food that is pivotal for the sur-
vival of the organism.
AD and epileptic activity
The incidence of unprovoked seizures is clearly higher
in sporadic AD than in reference populations with impli-
cations for memory functions. Nonconvulsive epilepti-
form activity could underlie at least some of the cogni-
tive impairments observed in AD. Up to 1 in 5 patients
with sporadic AD has at least 1 unprovoked clinically
apparent seizure during their illness, and clinical guide-
lines recommend obligatory treatment for this condition.
The risk of epileptic activity is greater in early-onset AD.
Many mutations in the presenilin-1 gene are associated
with epilepsy. Trisomy-21 patients with early-onset AD
also have frank seizures in 84% of cases. Many patients
with AD show fluctuations in cognitive functions such as
transient episodes of amnestic wandering or disorienta-
tion. While an intermittent inability to retrieve memo-
ries cannot be easily explained by relatively protracted
processes such as neuronal loss, plaque deposition, or
tangle formation, an abnormal epileptic activity of neu-
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Clinical research
ronal networks can. Extensive work in this field was
published by the group of Lennart Mucke. They see the
possibility that high levels of β-amyloid induce epilepti-
form activity, which triggers compensatory inhibitory
responses to counteract overexcitation that lead to
changes in synaptic circuitry and an increase in
inhibitory activity in, eg, the temporal cortex. This leads
to changes in the texture of the neural networks
involved and might explain disruptions of the networks
as seen in the default mode network (DMN) in AD.58-60
Transynaptic progression of toxicity effects of β-amyloid
inducing epileptic activity from the entorhinal cortex to
other brain regions may explain cognitive dysfunctions
in AD.61
The default mode network
AD affects the default mode network (DMN). This net-
work comprises brain regions that are active and inter-
connected in a wakeful state when the mind is not
focused on something specific. Anatomically it includes
part of the medial temporal lobe, the medial prefrontal
cortex, the posterior cingulate cortex, ventral precuneus,
and the medial, lateral, and inferior parietal cortex. This
networks develops during childhood and adolescence
and reaches full integration in adults, characterized by
coherent infraslow EEG oscillations smaller than 0.1 Hz.
The DMN is linked to other low-frequency resting state
networks in the brain and is anti-correlated with the ven-
tral and dorsal attention network. Measurements of glu-
cose metabolism with positron emission tomography
(PET), of structural atrophy with MRI, and intrinsic and
task-evoked brain activity with fMRI in AD all suggest
an increasing disruption in the DMN.62
When AD patients undergo a FDG-PET the pattern of
hypometabolism often mirrors the same regions that
belong to the posterior parts of the DMN, namely the pos-
terior cingulate cortex, the retrosplenial cortex, inferior
parietal lobule, and the lateral temporal cortex.63 Such
hypometabolism correlates with the mental status while
AD progresses.64 Probands with a genetic risk for AD of
being homozygous for ApoE4 develop this hypometabo-
lism already quite early in the course of the disease.62,65
Disruption in the DMN at the preclinical stages of the dis-
ease by accelerated cortical atrophy affects the medial
temporal lobe and the posterior cingulum and the retros-
plenial cortex.63,66 Also, analysis of task-induced deactiva-
tion and analysis of intrinsic activity correlations show an
450
impaired DMN consistent with metabolic and structural
changes.67-69 The DMN is coupled with hippocampus dur-
ing memory retrieval but not during memory encoding,
pointing to the special positioning of the hippocampus
between short-term and long-term memory.70 Encoding
structures of the DMN are among the first to show accu-
mulation of β-amyloid even before symptoms emerge and
images of β-amyloid plaques taken at the earliest stages of
AD show a distribution that is remarkably similar to the
anatomy of the default network.71 Buckner et al speculate
that AD pathology forms preferentially throughout the
DMN and may be linked to DMN activity.63 Their basic
idea is that the DMN’s continuous activity augments an
activity-dependent or metabolism-dependent cascade that
starts the β-amyloid cascade in these brain regions. Hence,
memory would be affected preferentially by the disease
because the DMN is mainly relying on cortical structures
that are also vital to memory functions and “burns” them
during activity. Interestingly, ApoE4 carriers have also
been found to have a higher rate of activity in the DMN
at rest compared with ApoE2 or ApoE3 carriers, and
decreased connectivity.72-74 A successful connection of this
hypothesis with the β-amyloid hypothesis of AD may
require any kind of upregulation of β-amyloid during
neural activity. Indeed, there are some studies that may
support such a link. Cirrito et al showed that β-amyloid
increased following stimulation of the brain in mice
expressing human amyloid precursor protein. They
demonstrated that β-amyloid in the brain interstitial fluid
was dynamically and directly influenced by synaptic activ-
ity on a timescale of minutes to hours.75 This observation
suggests that synaptic activity can increase the presence of
extracellular β-amyloid. A further supporting observations
come from a new PET method of mapping glycolysis
based on measuring the ratio of oxygen to glucose con-
sumption. Vlassenko et al calculated the spatial distribu-
tion of the regional glucose use apart from that entering
oxidative phosphorylation.76 The so-called “aerobic gly-
colysis,” the process by which glucose is metabolized into
cellular energy, might be more closely associated with neu-
ronal or synaptic activity than the mere glucose utilization.
In humans, aerobic glycolysis represents 35% of the glu-
cose turnover in the brain of a newborn and 19% of the
glucose used in the brain of an alert adult.77 Certain asso-
ciation areas in the human brain retain elevated levels of
aerobic glycolysis in adulthood related to cognitive func-
tions such as the dorsolateral prefrontal cortex, which is
associated with working memory, and the ventromedial
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Memory loss in AD - Jahn
prefrontal cortex, the dorsomedial prefrontal cortex, the
posterior cingulate cortex, the inferior parietal lobe, the
lateral temporal cortex, and the hippocampus.62,76-79 In nor-
mal young adults aerobic glycolysis correlated positively
and spatially with β-amyloid deposition observed in indi-
viduals with Alzheimer’s dementia and cognitively normal
participants with already elevated β-amyloid levels, sug-
gesting a possible link between regional aerobic glycolysis
in young adulthood and later development of AD pathol-
ogy. The map of resting-state glycolysis correlated remark-
ably well with the distribution of amyloid plaques.76 On the
other side DMN activity and coherence is diminished dur-
ing deep sleep. Here only partial network involvement was
observed, with apparent decoupling of frontal areas from
the DMN.80 An important study by Kang et al used in vivo
micro-dialysis in mice and found that the amount of β-
amyloid in the interstitial brain fluid correlated positively
with wakefulness. The amount of interstitial β-amyloid also
significantly increased during acute sleep deprivation.
Furthermore, chronic sleep restriction significantly
increased, and a dual orexin receptor antagonist decreased
β-amyloid plaque formation in human amyloid precursor
protein transgenic mice.81 Interestingly, sleep deprivation,
which is known to impair memory storage and retrieval,
reduces default mode network connectivity and anti-cor-
relation with the default attention networks during rest
and task performance.82 Regarding AD subtypes,
Lehmann et al report that the posterior DMN and pre-
cuneus network are commonly affected in all AD variants,
whereas syndrome-specific neurodegenerative patterns
are driven by the involvement of specific networks outside
the DMN and characterize differentially early-onset AD
(anterior salience network), logopenic variant of AD (lan-
guage network), and posterior cortical atrophy (visual net-
work).83
Sleep and memory
Sleep and the functional connectome are overlapping
research areas. Neuroimaging studies of sleep based on
EEG-PET and EEG-fMRI are revealing the brain net-
works that support sleep. Such infraslow oscillations may
organize sleep-dependent neuroplastic processes includ-
ing consolidation of episodic memory, for example.
Picchioni et al found positive correlations between the
power in the infraslow EEG band and MRI blood oxy-
gen level-dependent (BOLD) response in subcortical
regions and negative correlations in the cortex. Robust
451
Dialogues in Clinical Neuroscience - Vol 15 . No. 4 . 2013
negative correlations were detected principally in para-
median heteromodal cortices whereas positive correla-
tions were seen in cerebellum, thalamus, basal ganglia,
lateral neocortices, and hippocampus.84 Sleep has adap-
tive and recreating functions that uphold waking activity
in humans and mammals in general. Our understanding
of DMN activity and its regulation during sleep may be
also important for our general understanding of phe-
nomena like memory, arousal, and consciousness.80,84-86
Clinically sleep-wake disturbances such as increased
inadvertent daytime napping and insomnia at night affect
25% to 40% of patients with mild-to-moderate AD.87
Even in mild cognitive impairment there are already
abnormalities in sleep architecture and electroen-
cephalography measures. Sleep changes in patients with
amnestic mild cognitive impairment may contribute to
memory deficits by interfering with sleep-dependent
memory consolidation.88
In a small study, Ju investigated sleep in 145 cognitively
healthy probands older than 45 years. Amyloid deposi-
tion, as assessed by β-amyloid levels, was present in 32
participants. This group had worse sleep quality, as mea-
sured by sleep efficiency compared with those without
amyloid deposition, after correction for age, sex, and
ApoE4 allele carrier status, while the quantity of sleep
did not differ between groups. Frequent napping, 3 or
more days per week, was associated with amyloid depo-
sition. The authors concluded that indices for amyloid
deposition in the preclinical stage of AD appears to be
associated with worse sleep quality.89
Taken together the brain activity patterns may directly
modulate the molecular cascades that are relevant to dis-
eases. In the case of AD, increased resting-state activity
may accelerate the formation of amyloid pathology.
This opens up perspectives for new interventions that
may take the form of a therapy that attempts to modify
glycolysis or other aspects of brain metabolism or to
boost prophylaxis by the promotion of healthy sleep
behavior or working behavior.
Conclusion
For the clinician the easily applicable neuropsycholog-
ical test batteries augmented by a test for olfactory
recognition continue to be at the heart of the diagnos-
tic process for dementias, although new methods like
CSF analyses or MRI volumetry are increasingly avail-
able and validated for clinical use. The use of amyloid-
14 CH 8003 BA_INTERIEUR.qxd:DCNS#55 2/12/13 17:44 Page 452
Clinical research
tracer PET or fMRI to investigate, for example, the
DMN are still more preclinical than clinical character.
Despite enormous progress in our knowledge of some
pathophysiologic mechanisms in the last decade, we are
still far from understanding AD and also probably from
finding a cure. The available medications or medications
may, however, help us to manage some symptoms for
our patients, and gain some time for them. To date the
recent scientific advancements primarily offer earlier
diagnosis. With new diagnostic criteria properly applied,
we will likely be able to diagnose Alzheimer’s disease
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Memory loss in AD - Jahn
Pérdida de memoria en la Enfermedad de
Alzheimer
La pérdida de memoria está entre los primeros sín-
tomas referidos por los pacientes que padecen
Enfermedad de Alzheimer (EA) y por sus cuidado-
res. La memoria de trabajo y la memoria declara-
tiva de largo plazo se afectan precozmente
durante el curso de la enfermedad. El perfil indivi-
dual de deterioro de las funciones de la memoria
se correlaciona con parámetros de integridad cere-
bral estructural o funcional. La patología de la EA
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nivel molecular hasta el sistema de redes neurales.
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